Within the pharmaceutical art, the formulation of pharmaceutically active compounds into usable dosage forms, in which the absorption of the active ingredient is optimized and the extent of controllable side effects is minimized, is challenging to pharmaceutical formulation scientists and, frequently, unpredictable. In particular, pharmaceutical formulations for pharmaceutical agents having at least one acid moiety, preferably a carboxylic acid moiety, and which is soluble in acid at a ratio of about 30 to 1 (acid to solute) to about 10,000 to 1 [acid to solute; sparingly soluble to practically insoluble or insoluble (see, e.g., Sokoloski, T. D., Remington's Pharmaceutical Sciences, 16:208; 1990)] are generally known in the art to have less-than-optimum absorption and, in some instances, to cause otherwise controllable side effects upon administration to mammals. Representatives of these compounds include, for example, pharmaceutical agents well known in the art as non-steroidal anti-inflammatory drugs (NSAIDs), acetylcholinesterace ("ACE") inhibitors represented by the "pril" family, HMG-CoA reductase inhibitors represented by the "statin" family, histamine H.sub.1 -receptor antagonists such as, for example, fexofenadine, inhibitors of gastric acid secretion such as omeprazole, mast cell stabilizing agents, antihyperlipidemia agents, penicillins, antiacne agents, cephalosporins, including, for example, .beta.-lactams, salicylates, and a multitude of individual pharmaceutical agents.
For example, U.S. Pat. No. 4,880,835 describes the preparation of oral liquid compositions of calcium sulindac using a pharmaceutical vehicle comprised of a glycol, a polyol, and an optional alcohol. The patent further describes the well recognized problem of absorption of pharmaceutical agents, as described above, particularly NSAIDs, from the gut.
K. Chan, et al., Pharma Research, 7:1027 (1990) demonstrated that sodium diclofenac (an NSAID) was more orally bioavailable from an enteric coated tablet than from an aqueous solution. This is contrary to the expectation of the art and confirms the fact that a problem in the art exists. U.S. Pat. No. 4,704,405 also describes the problem of absorption of the above-described compounds, particularly NSAIDs such a sulindac, from the gastrointestinal tract.
N. M. Najib, et al., International Journal of Pharmaceutics, 45:139 (1988) have reported that ibuprofen-polyvinylpyrrolidone may form a weak acid-weak base type of complex in a solid state or in solution. This reference does not report any studies of the media or excipients used in the present invention.
U. K. Patent No. 2,059,768 describes the formation of more soluble derivatives of NSAIDs with the TRIS group of compounds.
Furthermore, U.S. Pat. No. 5,183,829 describes the preparation of NSAID formulations which appeared, in part, to improve adsorption of the pharmaceutically active agent while having positive effect on the aforementioned gastric side effects caused by NSAIDs. The patent describes a glycol-polyol media which can not be effectively used with soft gelatin capsules. More particularly, it was discovered that the polyols, and the concentration of polyols taught therein, caused the soft gelatin capsules to become tacky and adhere to adjacent soft capsules. This problem renders the pharmaceutical formulation taught in the '829 patent unviable when used in soft gelatin capsules.
Accordingly, the pharmaceutical formulations of the present invention represent a solution to the problems which result from formulations of the '829 patent as well as an advancement in the art of formulating pharmaceutically active substances into more elegant medicaments.